The proposed research is part of a long term effort to determine the mechanisms underlying the exaggerated bronchoconstrictor responsiveness that characterizes asthma. This project will combine methods of physiology, pharmacology and morphometry to study the mechanisms by which toluene diisocyanate (TDI), a widely used chemical that commonly causes asthma in exposed workers, induces both airway inflammation and airway hyperresponsiveness in guinea pigs. An advantage of this proposal is the long term collaborative interaction with a large group of scientists interested in the neurohumoral control of the lungs and airways. The general hypothesis we will test is that inflammation is a major mechanism of airway hyperresponsiveness. Thus, we will study the role of various aspects of the inflammatory response, including increased vascular permeability, chemical mediators of inflammation, and tissue infiltration with inflammatory cells, in the increase in airway responsiveness caused by exposure to TDI. First, we will use inhibitors of various steps in the metabolism of arachidonic acid to study the roles of prostaglandins, thromboxanes and leukotrienes in this response. By performing acetylcholine dose response curves and morphologic examination of sections of trachea and lung in treated and untreated animals exposed to air and to TDI, we will examine the effects of these inhibitors simultaneously on airway hyperresponsiveness and on morphologic evidence of airway injury and inflammation. Next, we will study the roles of polymophonuclear leukocytes (PMNs) in mediating the effects of TDI by performing similar studies in animals that have been depleted of PMNs or depleted and then repleted prior to exposure. We will perform similar studies in animals that have been depleted of eosinophils. In a parallel set of experiments we will study the role of inflammatory cells and mediators of inflammation in the increase in airway vascular permeability to Evans blue dye caused by exposure to TDI. Finally, we will study the effects of TDI on the in vitro behavior of airway smooth muscle both in the presence of and in the absence of PMNs eosinophils and airway epithelial cells. These studies should provide important insights into the mechanisms by which exposure to airborne chemicals can cause inflammation, edema, and hyperresponsiveness of the airways.